This proposal aims to understand the role of NKX2-1 amplification, the most common focal copy number alteration of lung adenocarcinoma, in the pathogenesis of this disease. Lung cancer is the leading cause of cancer death in the United States and lung adenocarcinoma is the most common type of lung cancer. NKX2-1 amplification occurs in approximately 12% of lung adenocarcinomas. NKX2-1 is required for the development of type II pneumocytes within the terminal respiratory unit, and is required for survival of lung adenocarcinoma cells in culture. Thus NKX2-1 exhibits many of the hallmarks of a lineage survival oncogene. The proposed research aims to understand the mechanisms by which NKX2-1 amplification contributes to lung adenocarcinoma pathogenesis, by accomplishing four specific aims. Specific Aim 1. Identify the transcriptional targets of NKX2-1 in lung adenocarcinoma. Specific Aim 2. Determine whether NKX2-1 is the only gene in the 14q13.3 amplicon that is required for lung adenocarcinoma cell survival. Specific Aim 3. Assess whether the LMO3 transcription factor gene is required for the survival of lung adenocarcinoma cells with and without NKX2-1 amplification. Specific Aim 4. Perform shRNA screens to identify cellular genes that are specifically required for the survival of lung adenocarcinoma cells with amplified NKX2-1 but not of cells that lack NKX2-1 expression. Through these aims, the proposed research will attempt to identify new therapeutic targets for the treatment of lung adenocarcinomas harboring NKX2-1 amplification. In this way, it should contribute to the broad goal of improving lung cancer treatment, which motivates this research program. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death in the United States and lung adenocarcinoma is the most common type of lung cancer. The purpose of our proposed research is to understand how one of the most common DNA alterations in lung adenocarcinoma contributes to causing this disease. This alteration is the presence of extra DNA copies of a gene that is required for lung development. We are trying to understand what other cellular genes are needed to help cancer cells survive when these extra gene copies are present but not when they are absent. Our hope is that this understanding will lead to improved diagnosis and treatment of lung adenocarcinoma.